The synergy of the XPO1 inhibitors combined with the BET inhibitor INCB057643 in high-grade B-cell lymphoma via downregulation of MYC expression

Abstract

AbstractHigh grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH) represents an uncommon B-cell lymphoma (BCL) with aggressive clinical courses and poor prognosis. Despite revolutionary therapeutic advances in BCL, there has been limited treatment progress in HGBCL-DH, thus necessitating additional therapeutic strategies for HGBCL-DH. This study demonstrated that the BET antagonist INCB057643 synergized with the XPO1 inhibitors (selinexor and eltanexor) to decrease cell viability and increase cell apoptosis in HGBCL-DH cells with or without TP53 mutations. As anticipated, the combined treatment of INCB057643 with selinexor slowed tumor growth and reduced the tumor burden in TP53-mutated HGBCL-DH xenografts. Mechanistically, MYC functional inhibition was a potential molecular mechanism underlying the synergy of the combined INCB057643 and selinexor treatment in HGBCL-DH cells independent of TP53 mutation status. In TP53 mutated HGBCL-DH cells, inducing DNA damage and impairing the DNA damage response (DDR) were involved in the therapeutic interaction of the combined regimen. In TP53 wild-type cells, the molecular mechanism was linked with upregulation of p53 levels and activation of its targeted pathways, rather than dysregulation of the DDR. Collectively, we might provide a potential promising combination therapy regimen for the management of HGBCL-DH. Clinical evaluations are warranted to confirm this conclusion.